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Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila.

Isaac, R. Elwyn and Johnson, Erik C. and Audsley, Neil and Shirras, Alan D. (2007) Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila. Journal of Experimental Biology, 210 (24). pp. 4465-4470. ISSN 0022-0949

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Abstract

Recent studies have firmly established pigment dispersing factor (PDF), a C-terminally amidated octodecapeptide, as a key neurotransmitter regulating rhythmic circadian locomotory behaviours in adult Drosophila melanogaster. The mechanisms by which PDF functions as a circadian peptide transmitter are not fully understood, however; in particular, nothing is known about the role of extracellular peptidases in terminating PDF signalling at synapses. In this study we show that PDF is susceptible to hydrolysis by neprilysin, an endopeptidase that is enriched in synaptic membranes of mammals and insects. Neprilysin cleaves PDF at the internal Ser7–Leu8 peptide bond to generate PDF1-7 and PDF8-18. Neither of these fragments were able to increase intracellular cAMP levels in HEK293 cells cotransfected with the Drosophila PDF receptor cDNA and a firefly luciferase reporter gene, confirming that such cleavage results in PDF inactivation. The Ser7–Leu8 peptide bond was also the principal cleavage site when PDF was incubated with membranes prepared from heads of adult Drosophila. This endopeptidase activity was inhibited by the neprilysin inhibitors phosphoramidon (IC50, 0.15 µmol l–1) and thiorphan (IC50, 1.2 µmol l–1). We propose that cleavage by a member of the Drosophila neprilysin family of endopeptidases is the most likely mechanism for inactivating synaptic PDF and that neprilysin might have an important role in regulating PDF signals within circadian neural circuits.

Item Type: Article
Journal or Publication Title: Journal of Experimental Biology
Uncontrolled Keywords: pigment dispersing factor ; neprilysin ; peptidase ; neuropeptide ; circadian rhythm
Subjects: Q Science > QH Natural history > QH301 Biology
Departments: Faculty of Science and Technology > Lancaster Environment Centre
Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 9418
Deposited By: Dr Alan Shirras
Deposited On: 09 Jun 2008 09:19
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 18:36
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/9418

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